Amino-acids, synthesis from carbonylation

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

Recently, we have demonstrated that 3 functions as an attractive chiral auxiliary for the synthesis of scalemic a-substituted carboxylic acids.22 In addition, we have extended the scope of the p-amino acid synthesis to include alkyl groups through a protected derivative of heterocycle 3.23 Thus, a unified approach to the synthesis of enantiomerically pure p-amino acids has been developed from 3. Recent efforts by Seebach, Juaristi, and co-workers24 on a saturated analog of 3 have developed routes to products substituted at C5 (a to the carbonyl). 

An earlier publication [312] described the synthesis of d,l-amino acid ester isocyanates (at that time called dj-carhonyl-amino acid esters) from the corresponding amino acid ester hydrochlorides by carbonylation with phosgene. Ester hydrochlorides of alanine, leucine, phenylalanine 451, aminobutyric add, phenyl glycine, norvaline, norleucine, benzyl cysteine, methionine, aspartic acid, and glutamic acid were used yields of isocyanates were 85-97%. 

The Petasis reaction represents a boronic acid variant of the Mannich reaction, and therefore is also referred to as a borono-Mannich reaction. It was first explored with formaldehyde as the carbonyl component and alkenyl, or ot,p-unsaturated organoboronic acid (III) as a nucleophile (route a in Scheme 8.2) [13]. It was later developed in a practical synthesis of a-amino acids (VI) from ot-keto acids (IV) and alkenyl boronic acids (III) [14] (route b in Scheme 8.2). 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The synthesis in Scheme 13.38 is based on an interesting kinetic differentiation in the reactivity of two centers that are structurally identical, but diastereomeric. A bis-amide of we.w-2,4-dimethylglutaric acid and a chiral thiazoline was formed in Step A. The thiazoline is derived from the amino acid cysteine. The two amide carbonyls in this to-amide are nonequivalent by virtue of the diastereomeric relationship established... 

A similar series of reactions was performed by Paulsen and Hdlck141 for the preparation of the T-antigenic, unprotected, amino acid-disaccha-rides 200 and 201, starting from the 4,6-0-benzylidene-N-(benzyloxy-carbonyl) benzyl esters 198 and 199, respectively, by condensation with 110 in the presence of mercury dicyanide-mercury dichloride and molecular sieves 4A, and deprotection of the product. Sinay and co-workers148 also reported the synthesis of hexa-O-acetyl derivatives of 200 and 201 by application of the sequence of azido-nitration-bromination. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

The elimination of water from (3-hydroxy-a-amino acid derivatives 28 is a particularly valuable method for the synthesis of DHAs 29, when the corresponding hydroxy compounds are readily accessible, such as, those of Ser, Thr and Ser( 3-Ph). 93 Some of the reagents recommended for the elimination of water are disuccinimidyl carbonate, 9495 l,l -carbonyl-diimidazole, 96 or a base and acetic anhydride. 97 Reaction of l,l -carbonyldiimidazole with arylidene Ser esters gives the corresponding DHA derivatives. 98 In the, presence of tri-ethylamine with terminally protected Ser and Thr residues in an inert solvent this reagent affords the AAla and AzAbu acid derivatives in good yields 96 (Scheme 10). This is perhaps one of the simplest and cleanest ways to prepare AAla and AAbu derivatives. 

Reetz et alJ33 described the stereoselective synthesis of partially protected a-hydroxy-y-amino acids 8 (Scheme 6) as potential pseudo-y-tum mimetics. X-ray diffraction structure analysis as well as NMR studies in CDC13 showed that these compounds display a pseu-docyclic eight-membered ring arising from an intramolecular H-bond between the amide carbonyl (i -1) and the alcohol hydroxy group (i). However, the ability of such a H-bond to induce or stabilize a pseudo-y-turn structure in an aqueous environment is doubtful. 

Support-bound 1,2-diamines can be readily converted into imidazolidinones by treatment with carbonyl diimidazole [128,129]. The required diamines have been prepared on cross-linked polystyrene by reduction of peptides bound to MBHA resin with borane. Similarly, bicyclic imidazolines have been prepared from triamines and thiocarbonyl diimidazole (Entry 10, Table 14.3). Dehydration of polystyrene-bound monoacyl ethylene-1,2-diamines yields 4,5-dihydroimidazoles (cyclic amidines, Entry 5, Table 13.18). Several groups have reported the synthesis of 2-aminoimidazol-4-ones from resin-bound amino acid derivatives (e.g., Entry 6, Table 15.11). Most of these compounds are, however, unstable, and slowly decompose if dissolved in DMSO (Jesper Lau, private communication). 

Soloshonok and co-workers have developed a method for the synthesis of a-(perfluoro-alkyl)amines from perfluoroalkyl carbonyl compounds by a transamination involving an azomethine a/omethine (Schiffbase) isomerization. They call this method a biomimetic, base-catalyzed 1,3-proton shift reaction, and have applied it to perfluoroaldehydes,12-15 perfluoroalkyl ketones,12 18 / -(perfluoroalkyl)-/l-oxo esters,15 16 19 24 and - -( perfluoroalkyl)-a-oxo es-ters2 " -26 to synthesize the corresponding a-(perfluoroalkyl)amincs, / -(perfluoroalkyl )-/i-amino acids, and 3 -(perfluoroalkyl)- x-amino acids. 

A further interesting case is provided by the synthesis of ninhydrin (Expt 5.99, cognate preparation) from indane-l,3-dione (Expt 7.9) in which the methylene group is activated by two adjacent carbonyl groups. Ninhydrin is the stable monohydrate of the triketone, indane-l,2,3-trione, and is a well-known colorimetric reagent for amino acids (Section 2.31). 

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